The technology that first enabled the synthesis of immunoglobulin molecules in tobacco plants is now being used to grow vaccines in fruits and vegetables. Although years from approval, this approach holds promise for people who fear needles and for countries that cannot afford to pay for distribution, storage, and delivery of costly injectable vaccines.
Researchers have had the most success cultivating food-borne vaccines against enteric diseases, particularly Escherichia coli and Norwalk virus. Hepatitis B, rabies, rotavirus, and HIV are also being studied for potential vaccine development in produce.
In August, the U.S. Food and Drug Administration granted approval to begin the first study of edible vaccines, using potatoes with the E. coli subunit vaccine, in human volunteers. The study should begin in the fall.
The technology to create these vaccines stemmed from genetic engineering techniques used to build disease resistance in crops. Charles Arntzen, PhD, president of Cornell University's Boyce Thompson Institute for Plant Research in Ithaca, New York, and his colleagues have created transgenic produce by first incorporating DNA from a human pathogen into single plant cells. New plants grown from those cells carry the pathogen's protein and pass it on to successive generations.
Unlike attenuated vaccines that pose a slight risk for infection, these edible varieties carry only an innocuous subunit of the pathogen, according to Arntzen, a pioneer in the attempt to incorporate vaccines in bananas.
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Hope for Developing Nations
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The quest for an edible vaccine was prompted in 1992 by a call from the World Health Organization for new, inexpensive vaccines for global immunization of children. However, Arntzen anticipates that they will also be used to immunize adults. He chose bananas because they are cheap, plentiful, and popular worldwide.
The researchers initially targeted E. coli and Norwalk virus because these organisms are endemic in developing countries. According to microbiologist John Clements, PhD, of Tulane University School of Medicine in New Orleans, 3.1 million people died from diarrheal disease in 1995.
In the United States, Arntzen envisions the edible vaccines being distributed among groups at high risk for enteric diseases, such as military personnel, travelers to developing countries, children at day care centers, and nursing home residents. Injectable vaccines have historically offered limited protection against enteric diseases, which attack the digestive mucosa, not the bloodstream. "If you're going to evoke mucosal defense, you need mucosal immunization," Clements said. "The most effective way to generate immunity against pathogens that act on the mucosal surface is with an edible vaccine."
Researchers at the Boyce Thompson Institute started with potatoes for their prototype vaccine because the tubers grow more quickly than bananas, their genetics are better understood, and mice will eat them raw.
"We fed it to mice and measured their antibodies," Clements said, referring to the potato E. coli vaccine (Science. 1995; 268:714-16). "We challenged them with the toxin that causes diarrhea, and they're okay. We have substantive proof you can induce a protective response."
One early question surrounding edible vaccines was the possibility that patients would develop oral tolerance. The validity of this concern awaits clinical testing, but studies of mice have shown immune response after several exposures to the potato vaccines. "We've given mice multiple oral doses and they've mounted an immune response each time," said biochemist Judith Ball, PhD, of Baylor College of Medicine in Houston. Ball has been studying mice that are fed potatoes containing Norwalk virus vaccine.
Because cooking destroys the vaccine protein and few people eat raw potatoes, Arntzen's staff hopes to graduate from potatoes to bananas. But the first crop of transgenic bananas, like the first potatoes, had too little viral protein. Researchers then created a more "plant-like," synthetic version of E. coli that Arntzen claims increased the concentration of vaccine in each potato 40-fold. He expects a similar increase in the bananas exposed to the altered gene, although it may take about 2.5 years to accomplish.
"To produce a significant amount of protein in bananas is difficult," Arntzen said. But he added with confidence, "If it worked with potatoes, it will work with bananas." He predicts one banana will yield up to 10 vaccine doses, bringing the cost of a vaccine down to less than one cent.
Researchers are testing the immune response of mice to several other vaccines in vegetables and fruit. Yasmin Thanavala, PhD, of the Roswell Park Cancer Institute in Buffalo, New York, is focusing on hepatitis B because the cost of the injectable vaccine is prohibitive in countries where the disease is most prevalent.
Thanavala has evoked a weak immune response to the virus in mice fed transgenic potatoes. "We need to increase the amount of antigen expressed in the potato to provoke a strong and long-lasting immune response," she said. "It's a few years away, but I think the feasibility has already been demonstrated."
Peter McGarvey, PhD, an assistant professor of microbiology and virology at Thomas Jefferson University in Philadelphia, is studying the potential of edible vaccines for rabies and HIV. He doubts that the widely anticipated first AIDS vaccine will come in a fruit or vegetable, but he added, "It's important enough to try."
-Cynthia Washam
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